Developing a Cardiac MRI Guided Therapy for Hemorrhagic Myocardial Infarction

PROJECT SUMMARY Re-establishment of blood flow (reperfusion) in coronary arteries has reduced immediate death from acute myocardial infarction (MI). However, the long-term complications in the chronic phase of MI, especially chronic heart failure (CHF) culminating in major adverse cardiovascular events (MACE), have become epidemic. Currently, ~2 million MI patients in the US are living with CHF; their 5-year survival rate is ~50%. A long-established predictor of CHF is MI size, which is tied to time-to-reperfusion. Reperfusion therapy is lifesaving. Yet, advances in cardiac MRI (CMR) have shown that microvascular obstruction (MVO), - a form of reperfusion injury – is an independent predictor of CHF, and MVO is now known to carry a 4-fold greater risk for MACE than MI size. Investigations by us and others, have shown that there are two classes of MVOs, one with intramyocardial hemorrhage (IMH) and the other without it. IMH, where microvascular rupture following reperfusion therapy leads to extravasation of red blood cells into the interstitium, occurs only with MVO and is evident in ~40% of reperfused MI patients. There is a 10-fold greater risk of MACE in patients with IMH than those without MVO. Recently we led the development of the first tissue injury-based classification of MI which was endorsed by the Canadian Cardiovascular Society (released in 2023). The CCS Classification shows that not all acute MIs are the same and identifies IMH (CCS-Stage 4) as the most severe form of reperfusion injury in acute MI. Further, current post-MI medications are not specific to tissue injury; and have not shown any incremental benefit to the MI patients across the spectrum of tissue injury. Development of new therapies against reperfusion injury would require greater insight into how reperfusion injury evolves over time and contributes to adverse remodeling and CHF. In the past funding cycle, we elucidated the pathophysiology of reperfused MI with IMH (hMI) and closed key gaps in knowledge on chronic influence of IMH on the heart. We showed that hMI results in iron deposits (ferric nanocrystals), persistent inflammation well into the chronic phase (years after MI), fatty infiltration; and that chronic iron deposition is an independent marker of adverse remodeling. We also showed that an FDA-approved iron chelator, deferiprone (DFP), can reduce iron and fat within chronic MI, and support anatomical and functional recovery away from CHF. Following up on these significant achievements, here we propose the following specific aims: (1) to develop that a CMR approach that can reliably detect and serially quantify evolving substrates within the hMI zone; (2) to demonstrate the benefits of early versus delayed start to DFP therapy in hMI under controlled conditions; and (3) to determine whether DFP can safely decrease iron, fat infiltration and reduce adverse remodeling in hMI patients. Accordingly, this proposal aims to advance the first therapy for hMI and serve as the foundational basis for a randomized clinical trial that can broadly enable a treatment for MI patients at the highest risk for MACE.